Colorectal Polyps: The Disease, Diagnosis and Treatment
A colorectal polyp is a circumscribed mass of tissue that projects above the surface of the bowel mucosa. It is classified as pedunculated or sessile, depending on whether it contains a discrete stalk. While most small polyps are asymptomatic lesions detected only by screening or diagnostic studies, larger polyps, greater than 10 mm, may ulcerate and cause intestinal bleeding, as well as have malignant potential.
Colorectal polyps are extremely common in adults in Western countries, they are found in more than 30% of autopsies conducted on people greater than 60 years of age (Correa P., Gastroenterology 77:1245-1251 (1979)). The colonic polyp has been implicated as a precursor in the development of colorectal cancer (Morson B. C., Cancer 34:845-850 (1974)). Current data suggest a polyp to cancer sequence, with colorectal neoplasmic changes as a continuous process from normal mucosa, to adenoma, and then to carcinoma (Schottenfeld, D. & Winawer, S. J., Cancer: Epidemiology and Prevention, Philadelphia, W. B. Saunders, 703-727 (1982)).
Histologically, polyps are classified as neoplastic, i.e., adenomas, with malignant potential or as non-neoplastic, known as benign adenomas (Fenoglio, C. M. & Pascal, R. R., Cancer 50:2601-2608 (1982)). Approximately 70% of polyps removed at colonoscopy are adenomas, (Konishi, F. & Morson, B. C., J. Clin. Pathol. 35:830-841 (1982)) with the potential to become larger than 10 mm, and therefore, having the probability of becoming tumorigenic. It is, therefore, of great importance to identify colonic polyps and to treat them before they can become malignant.
Most commonly, polyps are described as sporadic, arising spontaneously in about a quarter of the population by age 50, with the prevalence increasing with age, and which may or may not result in colorectal cancer (Winawer, S. J., et al., Gatstroenterology 112:594-642 (1997)). Familial adenomatous polyposis (FAP), on the other hand, is an autosomal dominant, inherited disorder, characterized by the presence of hundreds of adenomatous polyps in young adults and in the eventual development of colorectal cancer (Schussheim, A., et al., Gastroenterol. Nutr. 17:445-448 (1993)).
Colonoscopy is considered the best method for detecting polyps accurately, especially those measuring less than 10 mm in diameter (Rex, D. K., et al., Gastroenterology 112:17-23 (1997)). Most polyps found during colonoscopy can be completely and safely removed by electrocautery (fulguration) (Knutson, C. D. & Max, M. H., Arch Surg 114:30-435 (1979)). Some complications, however, may develop during colonoscopy, most commonly perforation and bleeding, occurring in 0.1 to 0.2% of patients (Rankin, G. B., Gastrointestinal Endoscopy, Philadelphia, W. B. Saunders, 875-878 (1987)). In addition, it is not always possible to detect all polyps using colonoscopy because of the anatomy of the colon. In fact, in a recent study, it was shown that a carefully performed complete colonoscopy by an experienced examiner will miss an average of about 24% of polyps that are less than 10 mm in diameter (Rex, D. K., et al., Gastroenterology 112:24-28 (1997)).
Non-Steroidal Anti-Inflammatory Drugs and Colorectal Polyps
To overcome the current technical limitations of colonoscopy, and to avoid the need for surgical procedures, extensive research has been focused during the past decade on finding pharmacologic agents that might be used to treat or prevent colorectal polyps. Especially, the effect of non-steroidal inflammatory drugs (NSAIDs) on colorectal polyps has become of interest.
Epidemiological studies have shown that chronic aspirin use is associated with a 50-70 percent reduction in the incidence of colorectal cancer (Logan, R. F. A., et al., Br. Med. J. 307:285-289 (1993); Rosenberg, L., et al., J. Natl. Cancer Inst. 83:355-358 (1991); Thun, M. J., et al., New Engl. J. Med. 325:1593-1596 (1991); Suh, O., et al., Cancer 72:11171-1177(1993); Peleg II et al., Arch. Intern. Med. 154:394-399 (1994)). In addition, multiple animal studies have documented a chemoprotective effect of selected NSAIDs as judged by a reduction in the frequency and number of premalignant and malignant lesions (Reddy, B. S., et al., Cancer Res. 50:2562-2568 (1990); Reddy, B. S., et al., Carcinogenesis 14:1493-1497 (1993); Rao, C. V., et al., Cancer Res. 51:4528-4534 (1991); Craven, P. A., & DeRuberis, F. R., Carcinogenesis 14:541-546 (1992); Northway, M. G., et al., Cancer 66:2300-2305 (1990); Moorghen, M., et al., J. Pathol 156:341-347 (1988); Reddy, B. S., et al., Cancer Res. 47:5340-5346 (1987); Reddy, B. S., et al., Carcinogenesis 13:1019-1023 (1992); Skinner, S. A., et al., Arch. Surg. 126:1094-1096 (1991)). In a recent case study of a patient with villous adenomas of the cecum, who refused surgical resection, a course of NSAID therapy, using piroxicam, 30 mg weekly, showed dramatic and sustained regression of the premalignant adenomas for up to 20 months (Gowen, G. F., Dis. Colon Rectum 39:101-102 (1996)). In clinical studies of familial adenomatous polyposis, using the NSAID, sulindac, at a daily dose of 300 mg, taken systemically, it was shown that the number and size of colonic polyps was significantly decreased (Giardelio, F. M., et al., New Engl. J. Med. 328:1313-1316 (1993); Labaylle, D., et al., Gastroenterology 101:635-639 (1991); Waddell, W. R., et al., Am. J. Surg. 157:175-179 (1989)). In a small pilot study, in which sulindac or piroxicam was used against sporadic colonic polyps, however, there was no similar regression of adenomatous polyps (Ladenheim, J., et al., Gastroenterology 108:1083-1087 (1995); Hixson, L. J., et al., Am. J. Gastroenterol 88:1652-1656 (1993)). These results, however, were disputed in a more recent multicenter study of nearly 100 patients, with sporadic polyps of 4-12 mm. When sulindac, 300 mg daily, or sulindac, 150 mg daily, or placebo, were given for one year, it was demonstrated that sulindac, regardless of dose, induced regressions and prevented the progression of sporadic colorectal adenomas (DiSario, J. A., et al., Gastroenterology 112 (Suppl):555A (1997)).
NSAIDs and Apoptosis
The precise mechanism responsible for the anti-neoplastic effect of NSAIDs is unknown. A number of recent publications have suggested that NSAIDs may be accomplishing these chemoprotective effects by induction of apoptosis, the "programmed cell death" phenomenon (Savill, J., Eur. J. Clin. Invest. 24:715-723 (1994); Thompson, C. B., Science 267:1456-1462 (1995); Bright, J. and Khar, A., Biosci Rep. 14:67-81 (1994)). In 1965, Lockshin and colleagues introduced the concept of "programmed cell death" to describe the phenomenon that had long been observed in embryogenesis where certain predetermined cells in the embryo would die at a particular stage during development (Lockshin, R. A. and Williams, C. M. J. Insect Physiol. 11:123-133 (1965)). In 1972, Kerr et al., linked this concept with a mode of cell death, defined on strict morphological criteria such as the detachment of a cell from its substratum, coupled by the fragmentation of the nucleus and cytoplasm, in a process which, they termed "apoptosis." (Kerr, J. F. R., et al., Br. J Cancer 26:239-257 (1972)). This active cell death, under tight genetic control, is found in all tissues, and is responsible both for regulating cell number and type, as well as for disposing cells with damaged or mutant DNA. Defects in apoptosis, however, can lead to cancer, autoimmune disease and neurodegeneration (Pritchard, D. and Watson, A. J. M., Pharmacol Ther. 72:149-169 (1996)).
Defective apoptosis has been implicated in the pathogenesis of colorectal cancer. In 1995, Bedi et al. quantified the amount of apoptosis in frozen sections of biopsies of colorectal epithelium from normal mucosa, adenomas from patients with familial adenomatous polyposis, sporadic adenomas, and carcinomas by in situ nick end labeling of histopathological specimens cultured for up to 24 hours on plastic. There was progressive inhibition of apoptosis during the transformation of normal epithelium into carcinomas (Bedi, A., et al.,Cancer Res. 55:1811-1816 (1995)).
Additionally, other studies support the contention that NSAIDs may exert their effect on colorectal polyps and carcinoma by inducing apoptosis. Pasricha et al. investigated the rate of proliferation and apoptosis in the flat colorectal mucosa of patients with familial adenomatous polyposis after treatment with sulindac. No effects on proliferation were found, but the sulindac-treated group showed increased levels of colonic mucosal apoptosis (Pasricha, P. J., et al., Gastroenterology, 109:994-999 (1995)). Piazza et al. similarly demonstrated the induction of apoptosis in an HT-29 colon adenocarcinoma cell line following sulindac administration, but found no evidence of cell proliferation or differentiation (Piazza, R., et al., Cancer Res. 55:3110-3116 (1995)). In a clinical study, Lee found that there were increased levels of apoptotic bodies in colonic biopsies from patients with diclofenac-induced colitis (Lee, F. D., J Clin Pathol 46:18-122 (1993)).
Induction of Apoptosis via COX-2
The mechanism whereby an NSAID induces apoptosis may be attributed to its known inhibition of cyclooxygenase-2 (COX-2), an enzyme associated with the inflammatory process (Vane, J. R. and Botting, F. M., Inflamm. Res. 44:1-10 (1995)). Prostaglandins are synthesized by the cyclooxygenase enzyme, of which there are two known isoforms, COX-1 (Miyamoto, T., et al., J. Biol. Chem. 251:2629-2636 (1976)) and COX-2 (Simmons, D. I., et al., Proc. Natl. Acad. Sci. USA 86:1178-1182 (1989)). COX-1 is a constitutive enzyme expressed in many tissues including the gastric mucosa, whereas COX-2 is an inducible enzyme expressed in fibroblasts, macrophages and other cell types in inflammation (Masferrer, J. L., et al., Proc. Natl. Acad. Sci. USA 89:3917-3921 (1992); Lee, S. K., et al., J. Biol. Chem. 267:25934-25938 (1992)). Although NSAIDs can inhibit both COX isoforms, they are selective in their inhibition rates of these enzymes. Diclofenac sodium and piroxicam, for example, exert a strong inhibitory effect on COX-2, (Meade, E. A., et al., J. Biol. Chem. 268:6610-6614 (1993)) while sulindac mainly exerts an inhibitory effect on COX-1. It has been suggested that the GI side effects associated with NSAIDs relate to COX-1 inhibition, while the anti-inflammatory effects of NSAIDs, relate to COX-2 inhibition (Mitchell, J. A., et al., Proc. Natl. Acad. Sci. USA 90:11693-11697 (1994)).
The induction of apoptosis as a result of COX-2 inhibition by NSAIDs has been implicated in the observed effects of NSAIDs on colonic polyp regression. This possible relationship between COX-2 inhibition by NSAIDs and apoptosis was demonstrated in a study by Tsujii and DuBois (Tsujii, M. and DuBois, R. N., Cell 83:493-501 (1995)). They transfected a rat intestinal epithelial cell line with mRNA for COX-2, thereby inducing COX-2 over-expression, and showed that these cells showed increased adhesion to the extracellular matrix and became resistant to butyrate-induced apoptosis. The authors proposed that COX-2 over-expression enhances the induction of tumors by changes in cellular adhesion and apoptosis inhibition.
There is considerable evidence for the association of an inhibition of COX-2 activity or expression with polyp and/or tumor regression. It has been observed that the disruption of the COX-2 gene reduces the number of tumors in mice by more than six-fold. Additional treatment of these mice with drugs that selectively inhibit the COX-2 enzyme results in a marked reduction of tumor multiplicity (Oshirna, K., et al., Cell. 87:803-809 (1996)). COX-2 expression is elevated in intestinal tumors which develop in carcinogen-treated rats. Treatment of these animals with many different NSAIDs results in a marked decrease in tumor multiplicity (DuBois, R. N., et al., Gastroenterology Clinics of North America 25:773-391 (1996)). Taking all these results together, it appears likely that COX-2 may be involved in the adenoma to carcinoma sequence, and that both highly potent and selective COX-2 inhibitors (such as diclofenac sodium), and weak inhibitors of COX-2 (such as sulindac) may be effective in polyp regression in both FAP and in sporadic polyps.
Although sulindac is only a weak inhibitor of COX-2, sulindac itself may not be the active agent in these studies. Sulindac has two metabolites that are formed following extensive first pass metabolism. One metabolite, sulindac sulfone, is formed via an irreversible oxidation. The second metabolite, sulindac sulfide, is formed via a reversible reduction. These two metabolites are considered to be more active than the sulindac itself (Brogden, R. N. et al., Drugs 16:97-114 (1978)).
For example, the anti-inflammatory activity that is associated with sulindac is primarily attributed to the more active metabolite, sulindac sulfide (Kwan, K. C. et al., Acta Rheumatol. Belg. 1:168-178 (1977)). Sulindac sulfide is a potent inhibitor of COX-2 (Riendeau E. et al., Can. J. Physiol. Pharmacol. 75:1088-1095 (1997)). Sulindac sulfide has also been found to be effective against several biochemical markers for colon cancer. It has been demonstrated that sulindac sulfide is six times more potent than sulindac in reducing proliferation and inhibiting the cell cycle in HT-29 colon adenocarcinoma cells (Schiff, S. J. et al., Exp. Cell Res. 222:179-188 (1996)) and that sulindac sulfide induced cell cycle inhibition in SW480 colon carcinoma cells (Lemoine, M. et al., Gastroenterology 112 (suppl.): A673 (1997)). The other metabolite, sulindac sulfone, is relatively inactive and does not show any anti-inflammatory activity (Kelloff et al., J. Cell Biochem. 20 (suppl.): 240-251 (1994)) but has shown some anti-neoplastic activity (Piazza, G. A. et al., Gastroenterology 112 (suppl.): A638 (1977)).
The association of NSAIDs with polyp and/or tumor regression is clear. The evidence for COX-2 involvement is very strong; however, in addition, other mechanisms may also play a role.
Local Delivery of NSAIDs to the Colon
A disadvantage of most NSAID therapy for colorectal polyps is that the NSAID is given systemically, and for long periods. Prolonged high systemic concentrations of many NSAIDs can result in other complications unrelated to the polyp treatment. For example, such NSAID users have a three-fold greater risk of developing serious GI complications over non-NSAID users. It has been estimated that 20% to 40% of patients on systemic NSAID therapy develop peptic ulcers (Taha, A., et al., N. Engl. J. Med. 334:1435-1439 (1996)). It has also been estimated that 10,000-20,000 fatalities a year occur in the United States from NSAID-induced gastrointestinal disorders. Other adverse effects of NSAIDs include renal failure, hepatic dysfunction, bleeding and gastric ulceration. The side effects of NSAIDs are especially of concern in the elderly, the very population most at risk for the development of colonic polyps. Therefore, a need exists for an alternative method to target therapeutic concentrations of NSAIDs to the site of colonic polyps.
Sulindac, given orally as a tablet, is primarily absorbed through the gastrointestinal tract. The peak plasma concentration is reached about two hours after dosing (Swanson, B. N. et al., Clin. Pharmacol. Ther. 32:397-403 (1982)). As a result of sulindac's extensive first-pass metabolism to its active metabolites, the plasma concentrations of sulindac sulfide and sulindac sulfone will exceed the levels of sulindac within four hours after dosing. Thereafter, these metabolites will remain the two major components in the blood while the concentration of sulindac will rapidly taper off (Duggan, D. E. et al., Clin. Pharmacol. Ther. 21:326-335 (1977)).
It has been demonstrated that although sulindac that is administered orally is primarily absorbed into the blood, a certain amount reaches the colon. The sulindac that reaches the colon will be reduced by the colonic microflora exclusively to sulindac sulfide, resulting in a high lumenal concentration of sulindac sulfide in the colon (Hanif, R. et al., Biochem. Pharmacol. 52:237-245 (1996)). The sulindac sulfide that is formed will then be absorbed through the colon walls to the bloodstream. This premise is supported by the fact that sulindac sulfide appears in the plasma long after sulindac and sulindac sulfone have been excreted in the urine and feces and that these findings are not seen in patients who underwent a colectomy and ileostomy (Strong, H. A. et al., Clin. Pharmacol. Ther. 38:387-393 (1985)). It can be concluded that the intact colon plays a significant role in the sustained presence of sulindac sulfide in the blood and that deliverying the entire dose of the sulindac to the colon will result in a significant enhancement of the formation of sulindac sulfide over the less active metabolite, the sulindac sulfone.
Local Delivery of Drugs to the Colon
U.S. Pat. No. 5,498,608 (Johnson, L. K.) describes the use of 2-hydroxy-5-phenylazobenzoic acid derivatives for the treatment of colon cancer. The derivatives are prodrugs that are converted into an active antiinflammatory drug by the action of colonic bacteria. The use of these agents for the treatment or prevention of colon cancer is proposed.
U.S. Pat. No. 5,686,589, U.S. Pat. No. 5,401,774, U.S. Pat. No. 5,643,959, EP 485,171, EP 485,173, and EP 508,586 (Brendel, K.) describes conjugating drugs into a prodrug form with substituted fused ring phenylacetic acids as a mechanism to deliver the active agent, such as an NSAID, to a colonic polyp. Colonic bacterial enzymes then cleave the active agent from the macromolecule.
U.S. Pat. No. 5,686,105 and U.S. Pat. No. 5,686,106 (both to Kelm, G. R.) describe the use of polymers to coat an active agent for delivery to the colon. The polymers dissolve at about the time that the dosage form reaches the inlet between the small intestine and the colon, or thereafter in the colon. Examples of such polymers include Eudragit.RTM. L and cellulose acetate phthalate. Examples of the types of agents that can be provided to the colon in this manner include agents for the topical treatment of diseases of the colon, such as irritable bowel syndrome, Crohn's disease, ulcerative colitis and carcinomas. Examples of the specific active agents that are listed include nonsteroidal antiinflammatory drugs, and chemotherapeutics for treatment of carcinomas.
U.S. Pat. No. 5,464,633 (Conte, U., et al.) describes a tablet that consists of a core containing the active substance, and an external layer that is able to prevent the immediate release of the active substance. The external layer can be a natural and/or synthetic polymeric substance in the class of the erodible and/or gellable and/or soluble in an aqueous medium hydrophilic polymers and adjuvant substances. Lastly, the layer is surrounded by a gastroresistant and enterosoluble coating.